Subscribe to eTOC

How Best to Diagnose Small Fiber Neuropathy

Article In Brief

A new paper considers the usefulness of a combination of three methods used to diagnose small fiber neuropathy: clinical exam, quantitative sensory testing, and a skin biopsy test called intraepidermal nerve fiber density.

Amid growing interest in small fiber neuropathy comes a new study that attempts to identify the best method for diagnosing the often overlooked or misdiagnosed condition.

Having a firm approach to diagnosing small fiber neuropathy would not only be useful for evaluation of patients in the doctor's office, experts told Neurology Today, but also would be helpful in clinical trials to ensure that potential treatments for small fiber neuropathy are tested in patients who actually have the condition.

Small fiber neuropathy (SFN)—which primarily affects small sensory fibers in the skin but also autonomic fibers involved in the control of involuntary muscles—is typically characterized by pain, burning, and numbness, usually beginning in the feet and sometimes progressing upwards. While SFN is often linked to diabetes, it is also associated with a variety of other conditions, including connective tissue diseases, thyroid dysfunction and chemotherapy and other toxic exposures.

Because SFN can present in varying ways—from pins and needles to digestive discomfort and nausea to exertional intolerance—patients may bounce from one doctor to another looking for an explanation for their problems. In the case of fatigue and widespread chronic pain, patients may get an erroneous diagnosis of fibromyalgia or even have their complaints not taken seriously because the symptoms seem vague.

On the flip side, indiscriminate treatment of pain with narcotics, without a sound rationale for doing so, has been cited as a factor in the opioid epidemic that is ravaging many parts of the US.

According to the paper in the October 30 online edition of Brain, “the diagnostic criteria for small fiber neuropathy are not established, influencing the approach to patients in clinical practice, their access to disease-modifying and symptomatic treatments, the use of healthcare resources and the design of clinical trials.”

Diagnosis of SFN is generally made using a combination of factors, including patient history and clinical exam, as well as testing that may indicate degeneration of small nerve fibers. The new paper considers the usefulness of two such tests: quantitative sensory testing (QST), a non-invasive technique to detect damage to small nerve endings by assessing whether the patient can feel mild vibrations and hot and cold sensations, and a skin biopsy test called intraepidermal nerve fiber density (IENFD).


“We are suggesting that neurologists should reposition the bedside examination at the center of patients diagnostic workup rather than relying on findings from laboratory exams out of the clinical context.”—DR. GIUSEPPE LAURIA

The new paper considers the usefulness of a combination of three methods used to diagnose SFN: clinical exam; quantitative sensory testing (QST), a non-invasive technique to detect damage to small nerve endings by assessing whether the patient can feel mild vibrations and hot and cold sensations; and a skin biopsy test called intraepidermal nerve fiber density (IENFD). The test, which involves taking a sample of skin from the lower leg and examining it with light microscopy to measure neurite density, is also referred to as END (epidermal neurite density).

In the US, the skin biopsy test is considered the “gold standard” by many neurologists for diagnosing SFN, according Lan Zhou, MD, PhD, professor of neurology and pathology at Boston University School of Medicine, who was not involved in the current study but who recently published a review paper on SFN in Seminars in Neurology.

Study Design, Findings

For the new paper, researchers from the University of Milan and IRCCS “Carlo Besta” Neurological Institute included two groups of patients to determine the ideal approach for diagnosing SFN. First, they performed a reappraisal study of data published in 2008 on 150 patients with sensory neuropathy. That study was originally done to develop criteria known as the Besta criteria for diagnosing SFN. The researchers also performed a prospective and follow-up validation study of 352 new patients with suspected SFN, in which patients underwent a clinical exam and QST and skin biopsy.

The reappraisal study ruled out SFN in five of the 150 originally suspected of having the disorder. In the new group of suspected cases, 187 patients underwent the three diagnostic exams and a diagnosis of SFN was made in 79.6 percent of the patients, with a combination of two clinical signs and abnormal QST or IENFD testing as the strongest indicator, said the senior author of the paper Giuseppe Lauria, MD, professor of neurology at University of Milan.

The study looked also at how symptoms correlate with the result of the diagnostic testing. Researchers followed 38 patients with sensory symptoms but no clinical signs of SFN during examination, and 89.5 percent had normal results for both QST and IENFD, which remained normal after 18 months. This suggests neurologists should not rely on symptoms alone because they are not specific enough, Dr. Lauria said.

He said the validation study found that “the combination of at least two clinical signs along with QST and/or IENFD findings can more reliably lead to the diagnosis of SFN than the combination of abnormal QST and IENFD findings in the absence of clinical signs.”

“We are suggesting that neurologists should reposition the bedside examination at the center of patient's diagnostic workup rather than relying on findings from laboratory exams out of the clinical context,” Dr. Lauria said.

The paper noted that QST, when at least threshold for warm is measured at both feet, remains “a valid test to assess the diagnosis of SFN, though its diagnostic accuracy is lower than that of IENFD.”

Dr. Lauria cautioned in an email interview that too much of a reliance on skin biopsy could lead to an overdiagnosis of SFN, particularly in cases where clinical signs are unspecific.

Expert Commentary

Anne Louise Oaklander, MD, PhD, FAAN, associate professor of neurology at Harvard Medical School, said the new paper addresses an important topic, but she said that she did not share any enthusiasm for QST for diagnosing SFN.

“We believe that our ‘two of three’ paradigm could be useful to address the clinical practice. Similarly, it can increase the reliability of clinical trial results,” Dr. Oaklander said.

She said the testing is time-consuming and subjective, noting that “Even if it's done very carefully it's still the patient telling you ‘I feel this, or I don't feel this.’”

For these reasons, medical insurers in the US do not reimburse for QST, so it's not even an option for clinical use here, she said.

Dr. Oaklander, director of the Nerve Unit & Neuropathology Skin Biopsy Service at Massachusetts General Hospital, said that the American and European Academies of Neurology endorse skin biopsy as the best diagnostic test for SFN.

Dr. Oaklander, who published a review article on SFN in JAMA Neurology in September, said that a consensus set of diagnostic criteria is needed for SFN so that all practitioners and researchers in the field are “speaking a common language.”

“The problem is there has never been any formal case definition of small fiber neuropathy,” Dr. Oaklander said, noting that she and Dr. Lauria are both members of the Consortium on Clinical Endpoints and Procedures for Peripheral Neuropathy Trials. a public-private partnership with the US Food and Drug Administration (FDA), which is also sponsored by the National Institutes of Health.

The committee of global neuropathy experts will present the first consensus definition of SFN at the 2020 AAN annual meeting with publication soon after, Dr. Oaklander said.

“We are developing the ‘McDonald criteria’ for SFN,” she said. “They will move research on this common and disabling neurological disorder to the forefront of neurological research and awareness.”

Dr. Zhou, who is director of the Boston Medical Center Cutaneous Nerve Laboratory, said, “The new paper, while perhaps not definitive, is important because it is part of an overall desire to get everyone on the same page when it comes to diagnosing SFN.” She believes that skin biopsy is superior to QST for helping make a diagnosis of SFN.

“It is more objective and that is why more and more neurologists are using it,” particularly in the US, she said. Standards tools used to detect large fiber neuropathy—electromyography and nerve conduction study—are not good for diagnosing SFN.

Dr. Zhou said SFN neuropathy is getting more attention, though much still needs to be learned about the condition, which affects both adults and, to a lesser degree, children. She said neuropathy involving large nerve fibers is often more obvious because a patient may have muscle weakness or trouble walking.

She said SFN “can be annoying and debilitating because of the pain” and in the case of SFN-related autonomic dysfunction there can be dizziness or heart palpations, Dr. Zhou said. In general, treatment for SFN is aimed at treating the underlying cause. For instance, in SFN associated with diabetes, keeping good glucose control can spare more nerve damage.

Michael J. Polydefkis, MD, FAAN, professor of neurology at Johns Hopkins University who helped develop the skin biopsy test, said the new paper on diagnostic criteria for SNF was very important, though it had some limitations. It was done at a single center and the findings need to be replicated across multiple sites and shown to hold up in a clinical trial setting, he said. The study also specifically excluded patients with any signs of large fiber neuropathy and that might make identifying patients for clinical trials more challenging, he said.

“While the definition of SFN and diagnostic criteria are still being worked out, all neurologists agree on the basic principle, though some might quibble over some finer points,” Dr. Polydefkis said.

He said the ultimate goal is to find better ways to treat neuropathic pain and SFN has a bright future as a therapeutic target.


Drs. Lauria, Oaklander, and Zhou had no disclosures. Dr. Polydefkis has consulted for Alnylam, Akcea, Pfizer and Biogen, none of which are relevant to the current paper.

Link Up for More Information

• Devigli G, Rinaldo S, Lombardi R, et al. Diagnostic criteria for small fibre neuropathy in clinical practice and research Brain 2019; Epub 2019 Oct 30.
    • Zhou L. Small fiber neuropathy Semin Neurol 2019;39(5):570–577.
    • Oaklander AL, Nolano M. Scientific advances in and clinical approaches to small-fiber polyneuropathy: A review JAMA Neurol 2019; Epub 2019 Sep 9.